Background/Purpose: Development of effective targeting strategies to eliminate sources of antibody production presents utility in the treatment of autoimmune diseases driven by pathogenic autoantibodies. Furthermore, targeting antibody producing cells has potential benefit in settings where a pre-existing antibody response might hinder delivery of a therapeutic agent. To test the impact of B-lineage targeting approaches on a specific antigen-specific antibody response, we utilized an adeno-associated viral (AAV) model of in vivo gene transfer. Adeno-associated viral (AAV) vectors have emerged as safe and effective vehicles for in vivo gene transfer, yet, the full potential of AAV gene therapies has so far been limited by the either pre-existing or the development of host neutralizing antibodies (nAbs) against AAV capsid. Strategies to overcome anti-drug antibody responses have the potential to vastly expand the utility and accessibility of therapies limited by preexisting nAbs, in addition to potential for use in autoimmune diseases driven by pathogenic antibodies.

Methods: We tested if anti-AAV antibodies could be eliminated in vivo by plasma cell depletion with Linvoseltamab, a fully-human T cell-bridging bispecific antibody targeting B cell maturation antigen and CD3 (BCMAxCD3), either alone or in combination with B cell depletion (to eliminate additional sources of anti-AAV Abs) and/or therapeutic FcRn blockade (to accelerate serum IgG clearance). To model a scenario of strong pre-existing AAV immunity, we first treated dual CD3- and BCMA-humanized mice with AAV8 to induce high-titer anti-AAV Abs. Ten weeks later, we administered weekly doses of BCMAxCD3, anti-CD19/20 antibodies, and/or an FcRn blocking therapeutic and monitored anti-AAV IgG titers for five weeks.

Results: Mice treated with both BCMAxCD3 and FcRn blocker showed rapid anti-AAV IgG titer reductions to naïve or near-naive levels, and mice additionally treated with anti-CD19/20 antibodies universally exhibited undetectable titers after five weeks of treatment. Whereas treatment with BCMAxCD3, anti-CD19/20, or FcRn blocker alone elicited only minor titer reductions. Strikingly, upon administration of a second distinct AAV8 vector, 3/6 mice receiving BCMAxCD3 + FcRn blocker and 6/6 mice receiving all three agents achieved re-transduction at levels equivalent to seronegative control mice.

Conclusion: Collectively, these results suggest plasma cell depletion with BCMAxCD3 (+ FcRn blockade) can successfully target sources of antibody production and thereby eliminating a preexisting antigen-specific antibody response. Efficacy was further improved when combined with B cell depletion. Findings from this study provides insight into optimal strategies for durably eliminating an antigen-specific antibody response.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/distinct-b-cell-and-plasma-cell-immunosuppression-strategies-eliminate-antigen-specific-cells-of-the-b-lineage/